Elena Matteucci

Microalbuminuria and endothelial dysfunction in essential hypertension

Microalbuminuria (urinary albumin excretion between 20 and 200 micrograms/min) and endothelial dysfunction coexist in patients with essential hypertension. To evaluate whether the two phenomena are related and the determinants of that association, we recruited 10 untreated males with essential hypertension and microalbuminuria without diabetes to be compared with an equal number of matched patients with essential hypertension excreting albumin in normal amounts and 10 normal controls. The status of endothelial function was inferred from circulating von Willebrand Factor antigen (vWF), a glycoprotein secreted in greater amounts when the vascular endothelium is damaged. vWF concentrations were higher in hypertensive patients with microalbuminuria than in hypertensive patients without and controls. Individual vWF and urine albumin-excretion values were correlated (r = 0.55, p < 0.002). Blood pressure correlated with both urinary albumin excretion and vWF. Left ventricular mass index and minimal forearm vascular resistances were comparable in patients with hypertension and higher than in controls; total and low-density lipoprotein cholesterol, triglycerides, lipoprotein-a, Factor VII, and plasminogen activator inhibitor-1 did not differ. Fibrinogen was higher and creatinine clearance lower in microalbuminurics. Albuminuria in essential hypertension may reflect systemic dysfunction of the vascular endothelium, a structure intimately involved in permeability, haemostasis, fibrinolysis, and blood pressure control. This abnormality may have important physiopathological implications and expose these patients to increased cardiovascular risk.

Increased echodensity of myocardial wall in the diabetic heart: An ultrasound tissue characterization study

OBJECTIVES We sought to characterize myocardial echodensity in asymptomatic patients with insulin-dependent diabetes and normal conventional two-dimensional echocardiographic findings to determine whether ultrasound tissue characterization can detect ultrastructural changes in myocardium, such as an increase in collagen content. BACKGROUND Fibrosis alters the acoustic properties of the heart in animals and humans, and these changes are detectable by cardiac tissue characterization with ultrasound. Early changes detected in the diabetic heart include increased interstitial collagen deposition. METHODS Using two-dimensional echocardiography, we evaluated 26 asymptomatic patients with insulin-dependent diabetes with normal regional and global rest function, and 17 age- and gender-matched control subjects. By selection, all diabetic patients were normotensive and had negative maximal exercise stress test results to avoid the confounding effects of hypertension and coronary artery disease. Using an echocardiographic instrument implemented at the Institute of Clinical Physiology, we performed an on-line radiofrequency analysis to obtain quantitative operator-independent measurements of the integrated back-scatter signal of the ventricular septum and posterior wall. The integrated values of the radiofrequency signal from the myocardial wall were normalized for those from the pericardial interface and were expressed as percentages (integrated backscatter index). RESULTS Diabetic patients showed a significant increase in myocardial echodensity both in the septum ([mean +/- SD] 36.6 +/- 8.1 vs. 23.6 +/- 4.4, p < 0.0001) and posterior wall (21.2 +/- 5.3 vs. 18.4 +/- 3.7, p < 0.001). By individual patient analysis, 17 patients exceeded the 95% confidence limits for normal myocardial echocardiographic reflectivity found in normal subjects, and only 3 had a relatively abnormal transmitral Doppler filling pattern (E/A ratio), mainly consisting of an abnormally increased late peak flow velocity (65% vs. 11%, p < 0.001). The increased myocardial intensity was similar in patients with (n = 16) and without (n = 10) noncardiac complications, such as retinopathy or nephropathy (37.5 +/- 7.9% vs. 35.0 +/- 8.3%, p = 0.35). CONCLUSIONS Abnormally increased myocardial echodensity, possibly related to collagen deposition, can be detected in asymptomatic diabetic patients with normal rest function. Theoretically, this finding might be considered a very early preclinical alteration potentially related to subsequent development of diabetic cardiomyopathy.

Asymptomatic Bacteriuria in Women with Diabetes: Influence of Metabolic Control

We screened 228 women with diabetes for bacteriuria during the period of January 1997 through December 2000 at Pisa General Hospital (Pisa, Italy). A control group of 146 women without diabetes was also evaluated. The frequency of significant bacteriuria was 17.5% (40 of 228) among women with diabetes and 18.5% (27 of 146) among women in the control group. Seven (13.5%) of 52 and 33 (18.8%) of 176 women with type 1 and in type 2 diabetes, respectively, had significant bacteriuria. The presence of higher glycated hemoglobin levels was the only significant risk factor for significant bacteriuria in women with type 2 diabetes. A similar frequency of bacteriuria in women with and women without diabetes was found. Severe impairment of metabolic control of type 2 diabetes increases the risk of acquiring asymptomatic bacteriuria.

Thiol Signalling Network with an Eye to Diabetes

Redox regulatory system controls normal cellular functions. Controlled changes in redox couples potential serve as components for signal transduction, similarly to the phosphorylation cascade. Cellular redox biology requires both compartimentalisation and communication of redox systems: the thermodynamic disequilibrium of the major redox switches allows rapid and sensitive responses to perturbations in redox environments. The many oxidation states of sulphur are found in numerous sulphur species with distinct functional groups (thiols, disulphides, polysulphides, sulphenic, sulphinic and sulphonic acids, etc.), which participate in a complicated network of sulphur-based redox events. Human diseases such as diabetes mellitus and its cardiovascular complications have been associated with increased production of reactive oxygen species and perturbations of thiol redox homeostasis. The review surveys literature related to some etiopathogenic aspects and therapeutic perspectives. The dual toxic-protective property of sulphydryl-donor molecules in experimental settings proposes the general problem of designing antioxidants for therapeutic use.

Advanced oxidation protein products in plasma: stability during storage and correlation with other clinical characteristics

Abstract Proteins are susceptible to free radical damage. We measured advanced oxidation protein products (AOPP) in the plasma of 56 hospitalised patients. Concentrations of AOPP were expressed as chloramine-T equivalents by measuring absorbance in acidic conditions at 340 nm in the presence of potassium iodide. We also determined erythrocyte sedimentation rate (ESR), circulating urea, creatinine, glucose, uric acid, electrolytes, lipids, total proteins and fractions and fibrinogen. Twenty-four samples were processed both immediately and after 7, 15, 30, 90, 180 and 438 days of storage at both at −20°C and −80°C (aliquots were frozen and thawed only once) to evaluate AOPP stability. The remaining 32 samples were also processed for thiobarbituric-acid-reactive substances (TBARS). Mean AOPP concentration in all 56 patients was 48.3±37.2 μM. Mean basal concentration of AOPP in the 24 plasma samples (55.0±47.1 μM) showed no significant change at each intermediate determination, yet significantly increased after 438 days of storage both at −80°C (96.6±83.2, p<0.01) and, markedly, at −20°C (171.3±94.6, p<0.001). TBARS concentration was 1.59±:0.65 μmol/l. Multiple regression analysis evidence that AOPP concentration was positively correlated (multiple r=0.62, p<0.001) with serum urea and triglycerides, but negatively correlated with patient age (indeed, serum albumin and total proteins decreased with increasing age, r=0.3, p<0.05). TBARS concentration was associated with ESR and serum glucose (multiple r=0.73, p<0.001), yet positively with AOPP (r=0.39, simple p<0.05). We conclude that AOPP remain stable during sample storage both at −20°C and −80°C for 6 months. Renal failure and hypertriglyceridemia probably enhance the in vivo process of AOPP formation. Oxidative damage as measured by TBARS may be increased because of exposure to hyperglycemia causing nonenzymatic glycation of plasma proteins.

Insulin administration: present strategies and future directions for a noninvasive (possibly more physiological) delivery

Insulin is a life-saving medication for people with type 1 diabetes, but traditional insulin replacement therapy is based on multiple daily subcutaneous injections or continuous subcutaneous pump-regulated infusion. Nonphysiologic delivery of subcutaneous insulin implies a rapid and sustained increase in systemic insulin levels due to the loss of concentration gradient between portal and systemic circulations. In fact, the liver degrades about half of the endogenous insulin secreted by the pancreas into the venous portal system. The reverse insulin distribution has short- and long-term effects on glucose metabolism. Thus, researchers have explored less-invasive administration routes based on innovative pharmaceutical formulations, which preserve hormone stability and ensure the therapeutic effectiveness. This review examines some of the recent proposals from clinical and material chemistry point of view, giving particular attention to patients’ (and diabetologists’) ideal requirements that organic chemistry could meet.

Sitagliptin as add-on therapy in insulin deficiency: biomarkers of therapeutic efficacy respond differently in type 1 and type 2 diabetes.

Background Sitagliptin has been proven to be effective and safe as add-on to insulin in adult patients with type 2 diabetes and absolute insulin deficiency. Recently, it has been suggested to extend the use of dipeptidyl-peptidase-4 inhibitors to type 1 diabetes. The aim of this study was to evaluate and compare the effects of a long-term, fixed-dose combination of sitagliptin and metformin as add-on to insulin on body mass index, fasting plasma glucose, fructosamine, HbA1c, lipids, and daily dose of insulin in both type 1 diabetes and insulin-treated type 2 diabetes. Methods We recruited 25 patients with type 1 diabetes (mean age 51 ± 10 years, mean disease duration 26 ± 13 years) and 31 insulin-treated type 2 diabetic patients (mean age 66 ± 8 years, mean disease duration 19 ± 9 years), who received sitagliptin with metformin as a fixed-dose combination (50/1000 mg once or twice daily) or sitagliptin (100 mg once daily, if intolerant to metformin) in addition to ongoing insulin therapy for 46 ± 19 weeks and 56 ± 14 weeks, respectively. Results After 21 ± 9 weeks, patients with type 1 diabetes had a significantly lower body mass index, fasting plasma glucose, fructosamine, HbA1c, and daily insulin requirement. After 49 ± 17 weeks, they maintained their weight loss and total daily insulin dose and showed a significant reduction in low-density lipoprotein cholesterol levels, whereas their HbA1c had returned to baseline values. In patients with type 2 diabetes, long-term treatment remained weight-neutral but had persistent beneficial effects on short-term, intermediate-term, and long-term biomarkers of metabolic control, as well as on low-density lipoprotein cholesterol levels and insulin requirement. Conclusion Clinical outcomes differed according to type of diabetes in terms of quality and over time. In type 2 diabetes, the combination therapy significantly improved metabolic control and the lipid profile, and decreased insulin requirements, even in the absence of clinically significant weight loss. In type 1 diabetes, the combined therapy only temporarily improved metabolic control, but significantly decreased body weight, low-density lipoprotein cholesterol levels, and insulin requirements.

ERYTHROCYTE SODIUM/HYDROGEN EXCHANGE INHIBITION BY () EPICATECHIN

Epicatechin, a flavonoid belonging to the group of compounds collectively called catechins, have been reported to possess insulin‐like properties. Besides their anti‐diabetic properties, catechins also show growth inhibition. Since cytosolic pH (pHi) plays a role in cell proliferation and the Na/H exchanger (NHE) is the major pH (pHi) regulatory mechanism, we undertook in vitro studies with human erythrocytes to examine the effect of (−) epicatechin (EC) on the NHE1 isoform. NHE activity was measured in eight healthy volunteers, eight type 1 diabetics, and nine type 2 diabetics, following 30min incubations at 37°C with either 1m m epicatechin, 10−9m insulin or solvent alone. NHE activity was elevated in both groups of patients (P< 0.05). Epicatechin caused a 93% decrease in Na/H antiport activity in health controls, 89 and 86% in type 1 and type 2 diabetics, respectively (P< 0.001). Insulin caused a 36% decrease in antiport activity only in the type 2 diabetic group (P< 0.05). The strong inhibition of erythrocyte NHE1 (the ubiquitously present isoform) by epicatechin may have important implications. NHE1 inhibition could be one of the major mechanisms underlying the antiproliferative effects of catechins.

Systolic blood pressure response to exercise in type 1 diabetes families compared with healthy control individuals.

Objective Oxidative stress is increased in type 1 diabetes families. Since oxidative damage is a mediator of vascular injury and familial predisposition to hypertension increases the risk of hypertension and diabetic nephropathy, we studied blood pressure responses to exercise and cardiovascular risk factors in type 1 diabetes families. Methods Thirty-five type 1 patients, 74 first-degree relatives, and 95 healthy individuals without established coronary heart disease underwent a cycle ergometer test. Examination included medical history, lifestyle questionnaire, body weight, blood pressure, and laboratory tests [fasting plasma glucose and insulin, haemoglobin A1c (HbA1c), plasma lipids, C-reactive protein, fibrinogen, folate, plasma thiols, and albumin excretion rate]. Results Diabetic patients had higher plasma glucose, HbA1c, folate, and albuminuria, while lower plasma thiols than controls; relatives differed from controls in higher plasma total cholesterol and albuminuria, lower plasma thiols. No patient presented exercised-induced angina. Diabetic patients achieved a higher maximal exercise systolic blood pressure (similar workload); systolic pressure remained high during recovery. Relatives showed higher values of systolic pressure at peak exercise (same workload). The following were associated with an abnormal blood pressure response to exercise: diastolic blood pressure and HbA1c in the control sample; disease duration and fibrinogen in the diabetic group; plasma low-density lipoprotein (LDL) cholesterol, body mass index (BMI), housework, and plasma thiols among relatives. Conclusion An abnormal blood pressure response to exercise testing has been identified for the first time in asymptomatic normotensive non-diabetic relatives of type 1 diabetics, which was associated with indices of metabolic syndrome and oxidative damage. Moreover, in healthy normotensive non-diabetic control individuals (without a family history of type 1 diabetes), the systolic blood pressure response to exercise was significantly correlated with HbA1c levels.

Microalbuminuria and Erythrocyte Sodium-Hydrogen Exchange in Essential Hypertension

Microalbuminuria (urinary albumin excretion between 20 and 200 micrograms/min) and abnormalities of red blood cell sodium-hydrogen exchange coexist in essential hypertensive patients. To evaluate how the two phenomena relate, we recruited 10 untreated microalbuminuric male essential hypertensive patients without diabetes to be compared with an equal number of matched essential hypertensive patients excreting albumin in normal amounts as well as 10 healthy control subjects. Sodium-hydrogen exchange values were increased to a comparable extent in microalbuminuric and normoalbuminuric hypertensive patients. Systolic and mean blood pressures were higher in microalbuminuric patients. Fasting insulin was greater and high-density lipoprotein cholesterol lower in patients than control subjects. Urinary albumin excretion correlated positively with both mean blood pressure and left ventricular mass values in the absence of a relationship with circulating lipid and insulin levels. In contrast with microalbuminuria, sodium-hydrogen exchange covaried only with high-density lipoprotein cholesterol and insulin levels. Thus, microalbuminuria and an abnormal sodium-hydrogen exchange are unrelated phenomena in essential hypertensive patients. Microalbuminuria appears to be a hemodynamically driven biological variable, while an accelerated sodium-hydrogen exchange seems primarily conditioned by the metabolic abnormalities of hypertension, possibly in the context of an insulin-resistant syndrome.